At the same time, several genome-wide association studies that investigate the contribution of common genetic variation 12, 13, 14, 15 to COVID-19 have provided robust support for the involvement of several genomic loci associated with COVID-19 severity and susceptibility, with the strongest and most robust finding for severity being at the 3p21.31 locus 12, 13, 14, 15, 16. Further supporting this line of inquiry, rare loss-of-function variants in genes involved in the type I interferon response may be involved in severe forms of COVID-19 9, 10, 11. Genetic factors contributing to COVID-19 susceptibility and severity may provide new biological insights into disease pathogenesis and identify mechanistic targets for therapeutic development or drug repurposing, as treating the disease remains a highly important goal despite the recent development of vaccines. Although established host factors correlate with disease severity (for example, increasing age, being a man and higher body-mass index 1), these risk factors alone do not explain all of the variability in disease severity observed across individuals. One of the most remarkable features of SARS-CoV-2 infection is the variation in consequences, which range from asymptomatic to life-threatening, viral pneumonia and acute respiratory distress syndrome 8. The COVID-19 pandemic, caused by infection with SARS-CoV-2, has resulted in an enormous health and economic burden worldwide. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. They also represent potentially actionable mechanisms in response to infection. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3, 4, 5, 6, 7. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1, 2, host genetics may also be important. The genetic make-up of an individual contributes to the susceptibility and response to viral infection.
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